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Foundations of ART Management in Heavily Treatment–Experienced Patients
  • CME

Eric S. Daar, MD
Released: October 6, 2022

Clinical Studies of Newer Agents in Heavily Treatment–Experienced Patients: Lenacapavir

Lenacapavir is a capsid inhibitor in late stages of development. It's a new drug in a new class, so it is likely to be fully active in all patients. This is also a long-acting antiretroviral: It can be given as a subcutaneous injection every 6 months.

CAPELLA was a phase II/III trial of subcutaneous lenacapavir in heavily treatment–experienced patients.23,24 Those enrolled in the study had HIV-1 RNA ≥400 copies/mL with resistance to ≥2 agents from 3 of 4 main antiretroviral classes. They had ≤2 fully active agents available from the 4 main antiretroviral classes. This is a relatively small study, which is not surprising because the goal is primarily to see if the agent has intrinsic activity and to evaluate safety information.

There was a randomized cohort and a nonrandomized cohort. The randomized cohort received either oral lenacapavir (600 mg on Days 1 and 2 and 300 mg on Day 8) or placebo, both with their failing regimen. After Day 14, the group that received oral lenacapavir went on to receive lenacapavir subcutaneous injections plus an OBR for 52 weeks. The group that received placebo received the oral regimen of lenacapavir for 14 days, then received lenacapavir subcutaneous injections plus an OBR for 52 weeks.

The nonrandomized group simply received oral lenacapavir (600 mg on Days 1 and 2 and 300 mg on Day 8) plus OBR and, then after Day 14, received lenacapavir subcutaneous injections plus an OBR for 52 weeks.

Virologic suppression in the randomized cohort at Weeks 26 and 52 was very high: >80% in this highly treatment–experienced patient population.23,24 Similar results were seen at Week 26 in the nonrandomized cohort.

This trial suggests that lenacapavir given every 6 months along with an OBR in highly treatment–experienced, multidrug-resistant patients can achieve high virologic suppression rates.

An analysis was performed of virologic suppression rates and the relationship with the number of active drugs in the background regimen.23 It’s clear in this case that one achieves a higher suppression rate with more active drugs in the regimen. At Week 52, 94% of those who had 2 fully active agents in the OBR had HIV-1 RNA <50 copies/mL; 79% of those with only 1 active drug achieved this endpoint and with no active agents, 67%. Ideally, this drug will not be given alone but preferably with ≥1 other fully active drug. 

Resistance to lenacapavir does occur. The table in the slide summarizes the proportion of people who met criteria for resistance testing, and there was a subset of individuals who did indeed develop lenacapavir resistance.

Lenacapavir and all other new drugs in new classes should be used carefully in this patient population. We must ensure there are other active drugs in the OBR to minimize the risk of selecting for resistance that would limit treatment options for the future.

These are some of the safety data for lenacapavir that were recently presented at the 2022 International AIDS Conference.25 These are data specifically on injection-site reactions in the CAPELLA study and the CALIBRATE study (a phase II open-label study in treatment-naive persons).

Approximately 10% to 30% of people receiving subcutaneous lenacapavir report injection-site reactions; these were primarily grade 1/2. The incidence of reported injection-site reactions was less common after the second injection and most participants continued treatment. The number of patient who discontinued lenacapavir in either of the studies because of injection-site reactions was small.

The types of reactions reported and their duration are detailed in the table. Most lasted for fewer than 10 days. Nodules and induration did occur in select patients with evidence on biopsy that this was a foreign-body reaction.

Highly treatment–experienced patients are relatively uncommon in the current treatment era. They typically have multiclass-resistant virus and do not have fully active high-barrier drugs to include in their regimen.

This setting calls for a very careful review of measured or inferred viral resistance and establishing which available drugs are likely to be fully or partially active. Ideally, the subsequent regimen should include 2 and preferably 3 fully active drugs.1

These situations may be difficult to manage. It is suggested that healthcare professionals with less experience with highly treatment–experienced patients reach out for consultation to help guide the management of these very challenging scenarios.1

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